MEDICINE AND HEALTH

Novel radiosensitizers found in “orphan receptors”


In the treatment of most malignant tumors, radiation therapy plays an important role. However, cancer cells’ resistance to ionizing radiation (IR), which leads to tumor recurrence and metastasis, is the main cause of radiotherapy failure.

GPR162 (G protein-coupled receptor 162) belongs to the rhodopsin class A orphan receptor in G protein-coupled receptors (GPCRs), which is a very important membrane protein, which is abundantly expressed in brain and lung tissues and is closely related to the body’s dietary behavior and glucose metabolism, but its function is unknown.

The team of Tao Yongguang, a researcher at the Cancer Institute of the School of Basic Medical Sciences, Central South University, and Xiao Desheng, a professor in the Department of Pathology, School of Basic Medical Sciences, found in previous studies that lncRNA (P53RRA), inhibited by lymphoid-specific helicase (LSH), could upregulate GPR162 expression, and LSH was negatively correlated with the mRNA and protein expression levels of GPR162. It was suggested that LSH could regulate the role of GPR162 in tumors.

Their recent study confirmed that LSH can regulate the expression of GPR162, and that GPR162 can also play a role in tumors as a new tumor suppressor gene. The collaborative team found the protein STING (Stimulator of interferon genes) interacting with GPR162 through CO-IP combined mass spectrometry analysis, and confirmed that GPR162 is involved in regulating the non-classical pathway of STING and activating the type I interferon system. Finally, RNA-seq combined with some experiments further confirmed that DNA double-strand damage can activate the GPR162-STING-I interferon system, accelerate the DNA damage response in tumor cells, and then play a tumor inhibitory effect.

The team revealed for the first time that the orphan receptor GPR162 in the G protein-coupled receptor family can be used as a novel radiotherapy sensitizer, by interacting with STING, targeting the DNA damage response, activating IRF3 (Interferon regulatory factor 3), accelerating the activation of the type I interferon system, promoting the expression of chemokines such as CXCL10 and CXCL4, inhibiting tumor genesis and progression, and providing a new strategy for improving cancer radiotherapy.

Research mechanism diagram. Photo courtesy of interviewee

On February 1, the above results were published in Signal Transduction and Targeted Therapy, with Xiao Desheng, Tao Yongguang and Liu Shuang, a researcher at the Medical Research Center of Xiangya Hospital, as the co-corresponding authors of the paper, and Long Yao, a doctoral student at Central South University, as the first author.

The reviewers agreed that this was an interesting and innovative study. The researchers confirmed that GPR162 can act as a new tumor suppressor and radiotherapy enhancer, promote radiotherapy-induced DNA damage response, activate STING, and improve cancer radiotherapy. (Source: China Science News, Wang Haohao, Wen Jiamin)

Related paper information:https://doi.org/10.1038/s41392-022-01224-3



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